Octahydromorphanthridines

ABSTRACT

Novel octahydromorphanthridines of the formula:   WHEREIN X is hydrogen, chlorine or lower alkyl, n is 1 except when X is chlorine when n is 1 or 2, R is hydrogen or lower alkyl.

United States Patent [191 Simon et al.

[451 Sept. 16, 1975 OCTAHYDROMORPHANTHRIDINES [73] Assignee: Carter-Wallace, Inc., New York,

[22] Filed: Dec. 6, 1974 [21] Appl. No.: 530,275

[52] US. Cl. 260/239 D; 424/244 [51] Int. Cl. C07D 223/20 [58] Field of Search 260/239 D [56] References Cited UNITED STATES PATENTS 2,861,987 11/1958 Martin et al. 260/239 D 3,153,652 10/1964 Drukher et a1 260/239 D 3,316,245 4/1967 Drukher et al. 260/239 D 3,316,246 4/1967 Drukher et al. 260/239 D 3,381,000 4/1968 Drukher et a1. 260/239 D FOREIGN PATENTS OIR APPLICATIONS 834,281 5/1960 United Kingdom 260/239 D Primary Examiner-Donald G. Daus Assistant Examiner--D. B. Springer Attorney, Agent, or FirmKevin B. Clarke [57] ABSTRACT Novel octahydromorphanthridines of the formula:

N l R wherein X is hydrogen, chlorine or lower alkyl, n is 1 except when X is chlorine when n is l or 2, R is hydrogen or lower alkyl.

15 Claims, No Drawings 1 OCTAHYDROMORPHANTHRIDINES wherein X is hydrogen, chlorine or lower alkyl, n is 1 except when X is chlorine when n is l or 2 and R is by drogen or lower alkyl. As used herein and in the appended claims, the term lower alkyl shall mean alkyl radicals containing 1 to 6 carbon atoms.

These compounds can exist and can be used in the form of the free base or as an acid addition salt thereof prepared by treating the free base with a pharmacologically acceptable acid.

The l,2,3,4,4a,5,6,l la-octahydromorphanthridines, where X is hydrogen or lower alkyl and R is hydrogen, are obtained by the hydrogenation of the appropriate 5,6-dihydromorphanthridine in the presence of a suitable catalyst. The starting 5,6-dihydromorphanthridine can be secured by hydrogenating a morphanthridine in the presence of a suitable catalyst or by reducing a morphanthridin-6(5H)-one with a metal hydride such as lithium aluminum hydride or sodium bis(2-methoxyethoxy)aluminum hydride.

When it is desired to prepare a l,2,3,4,4a,5,6,l laoctahydromorphanthridine where X is hydrogen, one or two atoms of chlorine or lower alkyl and the nitrogen is substituted with a lower alkyl group, the appropriate octahydromorphanthridine is: l alkylated with an alkyl halide or (2) acylated with an acid halide or an acid anhydride and then reduced with a metal hydride chloroacetyl derivative, then chlorinating the amide under controlled conditions for monoor dichlorination, and finally removing the chloroacetyl group with hot alcohol solution containing dry hydrogen chloride gas.

The acid addition salts of the novel compounds of the invention are prepared by treating the free base with a pharmacologically acceptable acid in a suitable solvent.

Table l, which follows, sets forth the physical characteristics of a representative number of the novel compounds.

The following non-limiting examples are illustrative of the preferred methods for preparing a representative number of the novel compounds of this invention.

EXAMPLE 1 Preparation of 1,2,3,4,4a,5,6,l la-octahydromorphanthridine A mixture of 500 g (2.56 moles) or 5,6-dihydromorphanthridine, 10 g of platinum dioxide and 1400 ml of glacial acetic acid was hydrogenated in a stirring autoclave at ambient temperature and initial pressure of 500 pounds. After absorption of 2400 pounds of hydrogen, the solution was filtered and the acetic acid was removed under reduced pressure. The residual semisolid was dissolved in 21. of water, 15 g of charcoal was added and the mixture was filtered through diatomaceous earth. The filtrate was made strongly basic with potassium hydroxide, cooled and extracted into 31. of pentane. The pentane solution was dried over calcium sulfate, concentrated to l 1., chilled in a freezer overnight and filtered, yielding 350 g of l,2,3,4,4a,5,6,l laoctahydromorphanthridine, mp 4550C. This material was used in the next reaction without further purification. A sample prepared for analysis by recrystallization from pentane melted at 5 l52.5C.

Anal. Calcd. for C H N: C, 83.53; H, 9.51; N, 6.96.

Found: C, 83.32; H, 9.60; N, 6.98.

TABLE 1 Compound Recryst. Carbon Hydrogen Nitrogen C hlorinc No. X R Salt Solvent Mp, C Formula Calcd. Found Calcd. Found Calcd. Found Calcd. Found 1 H H HC1 Me CO 213-215 C H ClN 70.74 70.52 8.42 8.55 5.89 5.72 14.95 14.76 2 9-Cl H HC1 EtOAc- 235-240 C H CI N 61.77 61.60 7.04 6.86 5.14 5.18 26.05 26.21

CHCl:; 3 7.9- H HCI Me CO 284-285 C H CI N 54.83 55.05 5.92 6.00 4.57 4.60 34.68 34.70

diCl 4 8-CH. H HOAc Me CO 130-132 C H NO 74.14 73.63 9.15 8.92 5.09 4.72 5 9-C1 CH HCl EtOAc- 262 d. C, H ,CI N 62.94 62.90 7.39 7.30 4.89 4.84 24.76 24.80

CHCl;, 6 H CH HC1 Me Co 242-243 C H ClN 71.55 71.63 8.81 8.90 5.56 5.43 14.08 14.18 7 H C H HC1 MEK 230-231 C H ClN 72.29 72.49 9.10 9.21 5.27 5.36 13.34 13.14 8 H CH HCI Me CO 218-220 C H ON 73.57 73.48 9.60 9.70 4.77 4.72 12.06 12.18

or (3) reductively alkylated with an aliphatic aldehyde EXAMPLE 2 and formic ac1d or (4) reductively alkylated with an aliphatic aldehyde and hydrogen in the presence of a cat- Preparauon of I alyst l,2,3,4,4a,5,6,l la-octahydromorphanthrldme 65 hydrochloride (Compound I) The 9-chloro and 7,9-dichloro-octahydromorphanthridines can be prepared by first converting l,2,3,4,4- a,5,6,1 lu-octahydromorphanthridine to the 5- 65 g of the base, prepared as described in Example 1, was dissolved in 500 ml of ethanol, and the solution was treated with dry hydrogen chloride until pH 3 was reached. The solvent was removed in vacuo, and the residual oil was dissolved in acetone. The acetone solution was stirred for 3 hours, and the crystals that formed were removed by filtration. The hydrochloride, after drying at 100C, weighed 66.5 g.

EXAMPLE 3 Preparation of S-chloroacetyl-l ,2,3,4,4a,5,6,l la-octahydromorphanthridine A solution of 300 g (1.49 moles) of l,2,3,4,4a,5,6,l- 1a-octahydromorphanthridine in 600 ml of chloroform was cooled in an ice bath and stirred. 185 g (1.64 moles) of chloroacetyl chloride in 200 ml of chloroform was added dropwise over a period of 1.5 hours. The resultant solution was stirred and heated at reflux for 2 hours and then poured onto 1 kg of ice. The chloroform was separated and washed 3 times with water, dried over calcium sulfate and evaporated to a residual semisolid. On triturating with ethyl acetate, a crystalline product weighing 305 g was obtained. After recrystallization from ethanol, the purified product melted at Anal. Calcd. for C H ClNOz C, 69.16; H, 7.24; Cl, 12.76; N,5.()4.

Found: C, 69.31; H, 7.40; Cl, 12.57; N, 5.12.

EXAMPLE 4 Preparation of 9-chloro-5-chloroacetyl-l ,2,3,4,4a,5,6,l la-octahydromorphanthridine Chlorine gas (2.5 g, 0.036 mole) was bubbled into a cold solution of g (0.036 mole) of 5-chloroacetyl- 1,2,3,4,4u,5, 6,1 luoctahydromorphanthridine and 2 g (0.0123 mole) of ferric chloride in chloroform. The solution was allowed to stand overnight at room temperature, water was added and the organic layer was separated, dried and evaporated to dryness. The residual gum crystallized on triturating with methanol. The solid was recrystallized from methanol to yield 6 g of 9 chloro-S-chloroacetyl- 1 ,2,3,4,4u,5 ,6, l lu-octahydromorphanthridine, mp l48150C.

Anal. Calcd. for C H CI NO: C, 61.55; H, 6.13; CI, 22.71 ;l\l,4.49.

Found: C, 61.59; H, 6.19; Cl, 22.60; N, 4.70.

EXAMPLE 5 Preparation of 7,9'dichloro-5-chloroacetyll ,2,3,4,4a,5 ,6,1 la-oetahydromorphanthridine The chlorination of 5-chloroacetyl l,2,3,4,4a,5,6,l la-octahydromorphanthridine was carried out as described in Example 4 except that a 4 to 1 molar ratio of chlorine was used and the reaction mixture was allowed to stand for 48 hours instead of 24 hours. Water was added to the mixture and the chloroform solution was separated, dried and evaporated to dryness. Anhydrous ethyl ether was added to the residual oil and on standing crystallization occurred. The crystals were removed and recrystallized from methanol. The product melted at 146-148C.

Anal. Calcd. for C ,-H ,,Cl NO: C, 55.44; H, 5.23; Cl, 30.68;N, 4.04.

Found: C, 55.13; H, 5.32; Cl, 30.54; N, 3.91.

EXAMPLE 6 Preparation of 9-chlorol ,2,3 ,4,4a,5 ,6,l la-oetahydromorphanthridine hydrochloride (Compound 2) 10 g of 9-chloro-5-chloroacetyl-l,2,3,4,4a,5,6,llaoctahydromorphanthridine was dissolved in 150 ml of ethanol, and the solution was saturated with dry hydrogen chloride. The resulting solution was heated at reflux for 48 hours, evaporated to dryness, and the residue was dissolved in water. The aqueous solution was washed with chloroform, made strongly basic with sodium hydroxide, and the liberated base was extracted into chloroform. The chloroform solution was washed with water, dried over Drierite, and evaporated to dryness. The residue was dissolved in acetone, and the solution was treated with dry hydrogen chloride. Ether was added to induce crystallization, and the solid was removed, dried and recrystallized.

EXAMPLE 7 Preparation of 7.9-dichloro-l ,2,3,4,4a,5,6,l la-octahydromorphanthridine hydrochloride (Compound 3) 1.2 g of 7,9-dichloro-5-chloroacetyl l ,2,3,4,4 1,5,6,1 lu-octahydromorphanthridine was converted to 7,9-dichloro-l,2,3,4,4u,5,6,l la-octahydromorphanthridine hydrochloride as described in Example 6 except that ether was used instead of chloroform to wash the acidic aqueous solution and to extract the organic base after the addition of sodium hydroxide.

EXAMPLE 8 Preparation of 8-methyl-l ,2,3,4,4a,5,6,1 la-octahydromorphanthridine acetate (Compound 4) 8-Methylmorphanthridin-6(5H)-one (4.2 g) was mixed with 20 ml of a percent solution of sodium bis(2-methoxyethoxy)-aluminum hydride in toluene and 50 ml of benzene. The mixture was stirred and heated on a steam bath for 2 hours and then treated with 100 ml of 10 percent aqueous sodium hydroxide. The resulting mixture was extracted with ether and the organic solution was washed with water, dried, and evaporated to dryness yielding 4 g of crude S-methyl- 5,6-dihydromorphanthridiiie. The solid recrystallized from methanolmelted at l l3l 15C. The purified solid (1.3 g) was dissolved in 150 ml of glacial acetic acid and hydrogenated in the presence of platinum dioxide in a Parr hydrogenation apparatus. The mixture was filtered, concentrated in vacuo and the residue was recrystallized from acetone. The acetic acid salt melted at 130l32C.

Compounds 5 and 6 in Table l were prepared as described in Example 9.

EXAMPLE 9 Preparation of 9-chloro-5-methyll ,2,3 ,4,4u,5,6,l lax-octahydromorphanthridine hydrochloride (Compound 5) To a solution of 3.3 g of 9-chlorol ,2,3,4,4a,5,6,l laoctahydromorphanthridine in 10 ml of percent formic acid was added 5 ml of 37 percent aqueous formaldehyde. The solution was heated on a steam bath for 48 hours, and then ml of 10 percent hydrochloric acid was added. The solution waswashed with ether, made alkaline with 20 percent aqueous, sodium hydroxide and extracted with chloroform. The chloroform solution was washed with water, dried and evaporated to dryness. The oil was dissolved in anhydrous ether and treated with dry hydrogen chloride. The solid was re moved by filtration and recrystallized. Theproduct weighed l.3 g.

EXAMPLE Preparation of S-acetyll ,2,3,4,4a,5,6.l la-octahydromorphanthridine To a solution of 12.9 g of l,2,3,4,4a,5,6,l la-octahydromorphanthridine in 30 ml of pyridine and 50 ml of chloroform was added dropwise with stirring, 7.0 gof acetic anhydride. The mixture was stirred and heated under reflux for 1 hour and poured onto ice. Dilute hydrochloric acid was added and the chloroform solution was spearated. The aqueous solution was washed several times with chloroform, and the chloroform solutions were combined, washed with water, "dried and evaporated to dryness. The oil was triturated with isopropyl ether and the solid that'formed was removed and recrystallized from isopropyl ether. The purified amide weighed 9.0 g and melted at 82'84C.

Anal. Calcd. for C H NO: C,'78.97; H, 8.70; N, 5.76.

Found: C, 78.97; H, 8.68; N, 5.94.

EXAMPLE 1 1 Preparation of S-ethyl-l ,2,3 ,4,4a,5 ,6,l la-octahydromorphanthridine hydrochloride (Compound 7)" h A solution of 5 g of S-acetyl-l,2,3,4,4a,5,6,l laoctahydromorphanthridine in absolute ether was added dropwise with stirring to a mixture of 1.6 g of lithium aluminum hydride and tetrahydrofuran. The mixture was stirred at room temperature overnight. A small amount of ethyl acetate was added, and the mixture was poured into ice water. After filtering, the cake was washed with ether, and the organic layer of the filtrate was separated and extracted with 10 percent hydrochloric acid. The aqueous solution was made alkaline with 10 percent aqueous sodium hydroxide, and the liberated organic base was extracted into ether. The ether solution was dried and charged with dry hydrogen chloride. After recrystalization, the hydrochloride weighed 3.4 g.

EXAMPLE 12 Preparation of S-butyll ,2,3,4,4a,5,6,l la-octahydromorphanthridine hydrochloride (Compound 8) A mixture of 6.] g of l,2,3,4,4a,5,6,l la-octahydromorphanthridine, 4.2 g of butyraldehyde, 0.15 g of 5 percent palladiumcarbon catalyst and 100 ml of ethanol was shaken with hydrogen in a Parr hydrogenation apparatus at approximately 60C. The catalyst was removed by filtration, and the filtrate was concentrated to dryness. The residue was dissolved in 10 percent hydrochloric acid, and the solution was washed with ether, made alkaline with 10 percent aqueous sodium hydroxide and extracted with ether. The ether solution was washed with water, dried and saturated with dry hydrogen chloride. The product, after recrystallization, weighed 1.9 g.

' then poured into water. Dilute hydrochloric acid was added, andthe solution was washed with ether and then made alkaline with 10 percent aqueous sodium hydroxide. The organic base was isolated and converted" to the hydrochloride'as describedin Example 12. Theproduct obtained by this method was identicalto the product prepared according to the procedure given in Example 12.

Example l4v illustrates the .method of alkylating a l ,2,3 ,4 ,4a,5 ,6,1 1a-octahydromorphanthridine with an alkyl halide.

' EXAMPLE 14 I Preparation of p S-ethyl- 1 ,2,3,4,4a,5,6,1 lq-octahydromorphanthridine hydrochloride (Compound 7 f l g of l,2,3,4,4a,5,6,l la octahydromorphanthridine, 0.85 g of ethyl iodide and 50 ml of acetone were stirred and heated at reflux for 2 hours. The solvent was removed; in vacuo and the residue was dissolved in water. 10 percent aqueous sodium hydroxide wasadded and the oil was-extracted into ether. The ether'solution was dried and evaporated to dryness. A sample of the solid residue was recrystallized from isopropyl ether giving the purified base of Compound 7 melting at 6869C. The remainder of the crude base was dissolved in acetone, and the solution was charged with dry hydrogen chloride. An equal volume of ether was added to induce crystallization. The solid was removed by filtration and recyrstallized from MEK. It was identical, in every respect, to the product obtained by the method described in Example 1 1.

The compounds of this invention are useful as diuretic agents. A description of the biological assay procedure employed in establishing the diuretic activity of a representative compound of the invention is as follows.

Diuretic Effect of Octahydromorphanthridine in Hydrated Rats Nonfasted, male, Charles River albino rats, weighing l20-l60 g, were used for the test. l,2,3,4,4a,5,6,l laoctahydromorphanthridine was given orally at a concentration which would provide the desired dose as indicated in Table ll in a volume of l ml/lOO g body weight. Immediately after drug dosing, the rats were hydrated by giving 25 ml/kg of tap water orally. Con trol rats received orally l ml/ g of 1 percent acacia followed by 25 ml/kg of tap water.

After dosing the rats were placed in pairs in metabolism cages without food or water. Urine was collected in graduate cylinders and 6 hours later total urine volumes were recorded. Samples were analyzed for urine electrolytes Na, K and Cl, and total microequivalents excreted was calculated. Ratio between drug volumes and control volume was also calculated.

5. A compound of claim 1 wherein X is lower alkyl and R is hydrogen. 7

6. A compound of claim 1 wherein X is lower alkyl and R is lower alkyl.

TABLE 1 l Diuretic Effect of 1,2,3,4,4u.5,6,1 la-Octahydromorphanthridine Hydrochloride (Compound l in Hydrated Rats Dose No. of Urine, p. eq/Liter p. eq/ 1' otal Vol. mg/kg PO Animals vol. ml pH Na K Cl Na K Cl Control 10 9.4 10.6 7.08 :0.07 27 Q 54 :6 32 i 256 :29 499 :43 300 25 10 15.9 :0.6 7.28 10.1 1 47 :4 56 fl 45 :4 727 :68 898 :61 724 :71 50 10 19.2 :LO 7.25 :().()7 56 i 49 fl 50 :4 1083 :61 945 :68 956 :71 100 10 17.3 10.4 7.51 105 74 :3

What is claimed is: l. A compound of the formula:

and the pharmaceutically accepted salts thereof wherein X is hydrogen, chlorine or lower alkyl, n is 1 except when X is chlorine n is l or 2 and R is hydrogen or lower alkyl.

2. A compound of claim 1 wherein X is hydrogen and R is lower alkyl.

'3. A compound of claim 1 wherein X is chlorine and R is hydrogen.

4. A compound of claim 1 wherein X is chlorine and R is lower alkyl.

thridine hydrochloride 

1. A COMPOUND OF THE FORMULA:
 2. A compound of claim 1 wherein X is hydrogen and R is lower alkyl.
 3. A compound of claim 1 wherein X is chlorine and R is hydrogen.
 4. A compound of claim 1 wherein X is chlorine and R is lower alkyl.
 5. A compound of claim 1 wherein X is lower alkyl and R is hydrogen.
 6. A compound of claim 1 wherein X is lower alkyl and R is lower alkyl.
 7. 1,2,3,4,4a,5,6,11a-Octahydromorphanthridine
 8. 1,2,3,4,4a,5,6,11a-Octahydromorphanthridine hydrochloride
 9. 9-Chloro-1,2,3,4,4a,5,6,11a-octahydromorphanthridine hydrochloride
 10. 7,9-Dichloro-1,2,3,4,4a,5,6,11a-octahydromorphanthridine hydrochloride
 11. 8-Methyl-1,2,3,4,4a,5,6,11a-octahydromorphanthridine acetate
 12. 9-Chloro-5-methyl-1,2,3,4,4a,5,6,11a-octahydromorphanthridine hydrochloride
 13. 5-Methyl-1,2,3,4,4a,5,6,11a-octahydromorphanthridine hydrochloride
 14. 5-Ethyl-1,2,3,4,4a,5,6,11a-octahydromorphanthridine hydrochloride
 15. 5-Butyl-1,2,3,4,4a,5,6,11a-octahydromorphanthridine hydrochloride 